Water-Accelerated Decomposition of Olefin Metathesis Catalysts

Water is ubiquitous in olefin metathesis, at levels ranging from contaminant to cosolvent. It is also non-benign. Water-promoted catalyst decomposition competes with metathesis, even for “robust” ruthenium catalysts. Metathesis is hence typically noncatalytic for demanding reactions in water-rich environments (e.g., chemical biology), a challenge as the Ru decomposition products promote unwanted reactions such as DNA degradation. To date, only the first step of the decomposition cascade is understood: catalyst aquation. Here we demonstrate that the aqua species dramatically accelerate both β-elimination of the metallacyclobutane intermediate and bimolecular decomposition of four-coordinate [RuCl(H2O)n(L)(=CHR)]Cl. Decomposition can be inhibited by blocking aquation and β-elimination.

O lefin metathesis is an exceptionally versatile catalytic means of forging carbon−carbon bonds, 1,2 with frontier applications spanning pharmaceutical manufacturing, 3 materials science, 4 and chemical biology. 5,6 Water is ubiquitous in all of these contexts, at levels ranging from contaminant to cosolvent. This is important because water is now known to limit metathesis productivity even for relatively robust ruthenium catalysts (Chart 1). For demanding reactions in water-rich media (e.g., protein modification via cross-metathesis (CM) 6 or assembly of DNA-encoded libraries (DEL) via ring-closing metathesis 5c,e (RCM)), the ruthenium complex must be used in significant stoichiometric excess, in part due to water-induced decomposition. Catalysis has been achieved only where the ruthenium complex is shielded in a lipophilic region. 5a,b,d Catalytic metathesis is desirable not merely for efficiency: in certain chemical biology applications (DEL being a prominent recent example), it is critical, because the spent catalyst triggers DNA degradation. 5c More broadly, understanding how water promotes decomposition of ruthenium metathesis catalysts is critical to expand opportunities in these and other forefront applications, in which water is either necessarily present or impractical to remove.
Metathesis in water has been described as a race against decomposition. 6c Productivity is low and declines as the proportion of water increases. For example, a record turnover number (TON) of 640 was reported for a ruthenium-cyclic (alkyl)(amino)carbene (CAAC) catalyst for metathesis in 1:1 H 2 O-MeOH: in neat water, TONs dropped to 200. 8 In stark contrast, TONs up to 350 000 have been achieved in anhydrous solvent. 9 For Ru-H 2 IMes catalysts, TONs for (R)CM in water are <100. 10,11 The O'Reilly and Matsuo teams drew the logical inference that the ruthenium species present in aqueous solution are both less active and less stable. 12,13 Decomposition of Ru-1 (Scheme 1a) or GIII was shown to commence with formation of an aqua complex (observed by UV-vis analysis at high water concentrations), with the ensuing pathways remaining speculative. Scheme 1a depicts the initial equilibrium (a classic aquation-anation exchange, where anation signifies replacement of bound water by the chloride counteranion). 14 Consistent with decomposition via an aqua species, 15 metathesis activity was restored by addition of chloride salts routinely used to shift the aquation equilibrium in biological media. 16 The challenges associated with metathesis in the presence of trace water (important for both bench-scale 17 and process 3 chemistry) have been viewed as an independent problem. Metathesis productivity is severely degraded even at low concentrations of water, including the micromolar limits encountered in water-immiscible aromatic solvents (standard media for metathesis). 18−22 It is unclear, however, whether aquation is relevant. The sole class of metathesis catalysts subjected to mechanistic study under such conditions are phosphine-stabilized Grubbs complexes, such as GII. Quantitative elimination of [MePCy 3 ]Cl from GII in benzene-water supports an alternative mechanism, "donor-accelerated decomposition" (Scheme 1b). 23 That is, coordination of water accelerates loss of PCy 3 , which then abstracts the methylidene ligand as [MePCy 3 ]Cl.
Methylidene abstraction, however, is driven by the powerful nucleophilicity of PCy 3 . 24 This mechanism is irrelevant to the decomposition of phosphine-f ree catalysts such as HII, but the latter are no less vulnerable than GII in "wet" aromatic solvents 19−21 (indeed, fast-initiating variants are significantly more so). 19 We therefore set out to clarify the pathways by which water degrades phosphine-free catalysts, with an explicit focus on the mechanism operative at low proportions of water. We considered two limiting possibilities: (1) that decomposition would proceed via aquation as in Scheme 1a, at a slower rate (in which case identification of post-aquation deactivation steps would be relevant to decomposition by both bulk and trace water) or (2) that aquation would be too slow to contribute, enabling an alternative pathway to take over. Here we report evidence for aquation even at millimolar concentrations of water and present the first insights into the ensuing decomposition pathways. Water is shown to accelerate two pathways operative in anhydrous media: bimolecular decomposition (BMD) of methylidene species A and β-H elimination of the metallacyclobutane intermediate B (Scheme  1c).
We began by examining whether decomposition follows a different mechanism in water-saturated benzene 18 or if the pathway established in bulk water remains relevant. Building on the premise that decomposition commences with aquation and that added chloride salts inhibit this equilibrium reaction, 15 we examined metathesis productivity in benzenewater and the extent to which it is mitigated by added chloride ion. If aquation does not contribute to decomposition, we reasoned that TONs should be unaffected. As substrate, we chose N-tosyl diallylamine 1, the facile cyclization of which permits low catalyst loadings (50 ppm = 0.005 mol %; 5 μM Ru), hence providing an aggressive test of the impact of water.
The radar plots of Figure 1 give a straightforward visual comparison of the impact of water and chloride salt. The outermost (dashed) line indicates the maximum attainable TON of 20 000; deviations toward the center signify lower productivity. While RCM is near-quantitative for all catalysts but GII in dry benzene (gray line), TONs drop significantly in the presence of water (blue line). Maximum negative impact was seen for nG and HII, 25 and least for the iodide and CAAC catalysts, consistent with our prior report. 19 Addition of KCl had a beneficial impact in all cases (in the case of HII, TONs are tripled), but in no case is activity completely restored to anhydrous levels. This is unsurprising, given restrictions on partitioning of KCl into the organic phase. Clearly, however, the positive effect of chloride established in bulk water is maintained at the lower proportions of water examined herein. These data point toward aquation as an important initial step in water-induced degradation even when the catalyst is confined to the organic phase.
The increase for nGC1 Ph holds more specific mechanistic significance. Whereas Ru-NHC catalysts undergo both decomposition pathways shown in Scheme 1c, an exceptional feature of the CAAC catalysts is their immunity to β-H elimination, but not bimolecular coupling. The higher productivity of nGC1 Ph in the presence of added KCl thus implies that water-promoted BMD proceeds via an aqua  Table S1; ±2 in replicate runs. Addition of N n Bu 4 Cl was less effective: see Figure S1. complex. Also noteworthy is the resistance of the iodide complexes to decomposition by water. This may reflect the greater covalency of the Ru−iodide bond, which has been found to inhibit aquation in other contexts. 26 The improved performance declines over time, however, owing to competing halide exchange with KCl. 27 We previously suggested 19 that the deleterious effects of water in metathesis primarily involve the active species, as also established in decomposition by nucleophiles and Bronsted base. 29−31 Countering this hypothesis is the reported decomposition of the precatalysts Ru-1 and GIII in bulk water, as noted above. To resolve the discrepancy, we examined the stability of a series of precatalysts in anhydrous and "wet" benzene. In these experiments, the Ru complexes were stirred at 60°C without substrate: decreases in the intensity of the benzylidene signal vs internal standard (IS) were monitored for 48 h or until decomposition was complete.
Py-stabilized GIII was completely decomposed after 4 h in water-saturated benzene, as compared to just 9% in the anhydrous control reaction (Table 1, entries 1, 2). Indeed, in the absence of water, 25% GIII remains even after 5 days at 60°C . 7 Water has less impact on GII (entry 3), consistent with the low lability of PCy 3 . 32 For both GIII and GII, however, quantitative elimination of stilbene ( Figure S6) offers unequivocal evidence that water degrades these complexes by accelerating bimolecular decomposition. 7,33 (Nucleophilic attack of PCy 3 on the substituted alkylidene carbon is not observed, in contrast with the facile abstraction of methylidene ligands shown in Scheme 1b. 23 ) Equilibrium binding of water to form a spectroscopically unobservable, 34 organic-soluble aqua complex is proposed to accelerate dimerization via intermolecular H-bonding (see Ru-2a, Scheme 1c). 35 The chloride-bridged dimer Ru-2b was identified in computational studies of anhydrous BMD. 7 Neither HII nor nG underwent degradation after 2 days at 60°C (entries 5, 6). In contrast, the water-soluble HII analogue Ru-1 is reported to be completely decomposed after 16 h at RT in neat H 2 O (Scheme 1a). 12 We attribute the difference to the high concentrations of Ru and water under the literature conditions and a resulting shift of the aquationanation equilibrium to the right. Bimolecular coupling is extremely sensitive to steric bulk. 7,33 Given that water dramatically accelerates coupling of the benzylidene precatalysts GII and GIII, we anticipated that BMD would be the primary vector for catalyst decomposition in metathesis of terminal olefins in benzene-water, a reaction manifold propagated by methylidene species A (Scheme 1c, left). Unexpectedly, however, the rate of decomposition does not show a squared dependence on [Ru]; rather, it lies between first and second order ( Figure S3). We thus questioned whether water also promotes a second major decomposition pathway intrinsic to the majority of olefin metathesis catalysts: β-H elimination of the metallacyclobutane B (Scheme 1c, right). 36 To assess the impact of water on the latter pathway, we quantified the propenes eliminated during self-metathesis of styrene (Figure 2). Styrene is an invaluable substrate for this purpose because�unlike other 1-alkenes�it cannot isomerize to generate "false" propene markers. 7 Propene yields were assessed by quantitative 1 H NMR analysis at 24 h, 37 to ensure full catalyst decomposition.
No propenes (6a−c, Figure 2a) were detected for the CAAC catalyst nGC1 Ph in these experiments. In earlier studies conducted under anhydrous conditions, we reported that the CAAC catalysts, exceptionally, resist β-H elimination, 38 because the high trans-influence of the carbene destabilizes the transition state for decomposition. 39 The absence of propenes for nGC1 Ph indicates that water is unable to overcome this resistance. In contrast, the yields of 6a−c for the NHC catalysts increase in the presence of water, as indicated by the other data in Figure 2a. Hydrogen-bonding interactions between bound water and H β (see B′) are proposed to aid in the H-transfer step. The effect is greatest for HII and nG, which spend the most time in the active cycle. The inhibiting effect of added chloride on production of propenes (shown for HII in Figure 2b) is consistent with the involvement of an aqua species in the transition state for β-H elimination.
Among the NHC complexes, the bis-iodide catalysts (nG-I 2 , HII-I 2 ) underwent the least water-promoted β-H elimination, as anticipated from their relative water-tolerance. 19,40,41 This heightened stability may reflect the resistance of the Ru−I  bond to aquation, as discussed above. 42 Also of note are changes in the distribution of propene products in the presence of water. Higher yields of substituted 6b/c vs 6a (approximately double; Figure S2) could plausibly be due to faster reductive elimination from B′, owing to increased steric pressure by the iodide ligands on the substituted metallacyclobutane.
An unexpected feature of these experiments is the superstoichiometric yield of propenes with respect to the initial catalyst charge. We infer regeneration of active catalyst from decomposed ruthenium species. In situ installation of an alkylidene ligand�standard practice in ROMP prior to development of "well-defined" metathesis catalysts 43,44 �has recently been demonstrated for simple 1-olefins. 45 This observation holds considerable interest for the goal of recycling spent catalyst into the active cycle. 45,46 Nevertheless, the key point in the present context is the increase in propene yields in the presence of water, signifying enhanced β-H elimination.
Water has long presented an under-recognized challenge to metathesis reactions. Expanding interest in applications where water is inevitable has turned a spotlight on ruthenium−water interactions and their role in catalyst decomposition. In bulk water, chloride ion improves the productivity of Ru metathesis catalysts by reversing aquation. The foregoing establishes that aquation occurs even at low water concentrations (i.e., the same mechanism is operative in bulk and trace water) and offers the first insights into the ensuing decomposition cascade. The water ligand greatly accelerates two decomposition pathways operative even in anhydrous media: bimolecular decomposition of the methylidene intermediate and β-H elimination of the metallacyclobutane. 47 Recent discoveries that teach how to curb these pathways hence open the door to catalytic metathesis for demanding reactions in water. A high trans-influence ligand remains the key to inhibiting βelimination; classic anchoring strategies, or aquation-resistant ligands, will aid further. These insights are anticipated to create major new opportunities in chemical biology and other contexts where water is essential. ■ ASSOCIATED CONTENT